CN115010644B - 一种2,3-二取代吲哚啉类化合物的制备方法 - Google Patents
一种2,3-二取代吲哚啉类化合物的制备方法 Download PDFInfo
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- CN115010644B CN115010644B CN202210650796.XA CN202210650796A CN115010644B CN 115010644 B CN115010644 B CN 115010644B CN 202210650796 A CN202210650796 A CN 202210650796A CN 115010644 B CN115010644 B CN 115010644B
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- -1 2, 3-disubstituted indoline compound Chemical class 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000003054 catalyst Substances 0.000 claims abstract description 19
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910052802 copper Inorganic materials 0.000 claims abstract description 14
- 239000010949 copper Substances 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000012298 atmosphere Substances 0.000 claims description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 9
- 230000002829 reductive effect Effects 0.000 abstract description 8
- 229910052736 halogen Inorganic materials 0.000 abstract description 7
- 150000002367 halogens Chemical class 0.000 abstract description 7
- 125000001624 naphthyl group Chemical group 0.000 abstract description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 2
- 239000012467 final product Substances 0.000 abstract description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 2
- 239000001257 hydrogen Substances 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract description 2
- 238000005580 one pot reaction Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 24
- 239000000243 solution Substances 0.000 description 18
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000010586 diagram Methods 0.000 description 10
- 229910052786 argon Inorganic materials 0.000 description 7
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 4
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 4
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- XTQHKBHJIVJGKJ-UHFFFAOYSA-N sulfur monoxide Chemical compound S=O XTQHKBHJIVJGKJ-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 238000005913 hydroamination reaction Methods 0.000 description 2
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 2
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- ZXMGHDIOOHOAAE-UHFFFAOYSA-N 1,1,1-trifluoro-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)NS(=O)(=O)C(F)(F)F ZXMGHDIOOHOAAE-UHFFFAOYSA-N 0.000 description 1
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 1
- PSWDQTMAUUQILQ-UHFFFAOYSA-N 2-[(6-methoxy-4-methylquinazolin-2-yl)amino]-5,6-dimethyl-1h-pyrimidin-4-one Chemical compound N1=C(C)C2=CC(OC)=CC=C2N=C1NC1=NC(=O)C(C)=C(C)N1 PSWDQTMAUUQILQ-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- QBXVXKRWOVBUDB-GRKNLSHJSA-N ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C Chemical compound ClC=1C(=CC(=C(CN2[C@H](C[C@H](C2)O)C(=O)O)C1)OCC1=CC(=CC=C1)C#N)OCC1=C(C(=CC=C1)C1=CC2=C(OCCO2)C=C1)C QBXVXKRWOVBUDB-GRKNLSHJSA-N 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- SOWBFZRMHSNYGE-UHFFFAOYSA-N Monoamide-Oxalic acid Natural products NC(=O)C(O)=O SOWBFZRMHSNYGE-UHFFFAOYSA-N 0.000 description 1
- 229910021585 Nickel(II) bromide Inorganic materials 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000005035 acylthio group Chemical group 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 125000006323 alkenyl amino group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000006319 alkynyl amino group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- BZRRQSJJPUGBAA-UHFFFAOYSA-L cobalt(ii) bromide Chemical compound Br[Co]Br BZRRQSJJPUGBAA-UHFFFAOYSA-L 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125796 compound 3d Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 125000004986 diarylamino group Chemical group 0.000 description 1
- SCDCQWMBJXIYNA-UHFFFAOYSA-N diazocopper Chemical compound [N+](=[N-])=[Cu] SCDCQWMBJXIYNA-UHFFFAOYSA-N 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000006437 ethyl cyclopropyl group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- WRZZIMVMWOQUES-UHFFFAOYSA-N gold(1+);triphenylphosphane Chemical compound [Au+].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 WRZZIMVMWOQUES-UHFFFAOYSA-N 0.000 description 1
- 239000003630 growth substance Substances 0.000 description 1
- 125000000262 haloalkenyl group Chemical group 0.000 description 1
- 125000005291 haloalkenyloxy group Chemical group 0.000 description 1
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- 125000003106 haloaryl group Chemical group 0.000 description 1
- 125000004996 haloaryloxy group Chemical group 0.000 description 1
- 230000002363 herbicidal effect Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 125000006431 methyl cyclopropyl group Chemical group 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- IPLJNQFXJUCRNH-UHFFFAOYSA-L nickel(2+);dibromide Chemical compound [Ni+2].[Br-].[Br-] IPLJNQFXJUCRNH-UHFFFAOYSA-L 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004971 nitroalkyl group Chemical group 0.000 description 1
- 125000004999 nitroaryl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- CLSUSRZJUQMOHH-UHFFFAOYSA-L platinum dichloride Chemical compound Cl[Pt]Cl CLSUSRZJUQMOHH-UHFFFAOYSA-L 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 238000007154 radical cyclization reaction Methods 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- SVOOVMQUISJERI-UHFFFAOYSA-K rhodium(3+);triacetate Chemical compound [Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O SVOOVMQUISJERI-UHFFFAOYSA-K 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- CMTKJYPJPSONIT-UHFFFAOYSA-K trichlororuthenium;triphenylphosphane Chemical compound Cl[Ru](Cl)Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMTKJYPJPSONIT-UHFFFAOYSA-K 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
本发明公开了一种2,3‑二取代吲哚啉类化合物的制备方法,包括如下步骤:将式2所示的化合物与式3所示的化合物在铜催化剂和溶剂存在下进行反应,得到式1化合物;其中:R包括取代或未取代苯基、C1~8的烷基、卤素;R1包括取代或未取代苯基、取代或未取代萘基、C1~8的烷基、苄基、杂环取代基;R2包括氢、卤素、C1~8的烷基。本发明由式2所示的化合物与式3所示的化合物在铜催化剂和溶剂存在下进行反应,通过一锅法,即可制备式1的2,3‑二取代吲哚啉类化合物,该制备方法的原料廉价易得、操作方便、产率高。除了最终产物外,一系列转化过程中的中间体均无需分离和纯化,能减少资金和劳动力的投入,提供了一种简洁高效的制备方法。
Description
技术领域
本发明涉及有机合成技术领域,尤其是涉及一种2,3-二取代吲哚林类化合物的制备方法。
背景技术
氮杂环化合物是合成化学家的长期目标,因为它们是天然产物、药物和农药的多功能骨架。其中,吲哚啉作为N-杂环中独特的结构单元,在合成化学和药物化学中都具有重要的意义。在农业领域,吲哚类化合物可作为生长调节剂使用;一些含有吲哚结构单元的化合物也具有除草活性;吲哚啉螺环化合物可作为杀虫剂使用。其中功能化2,3-二取代的吲哚啉衍生物也备受人们关注,作为一类生物活性结构单元,普遍存在于生物碱和其它天然产物中,同时也可用于构建结构复杂的天然产物的起始原料。目前已报道的合成2,3-二取代吲哚啉衍生物的方法主要包括氢化还原,阳离子或自由基环化,金属催化的氢胺化,还原氢胺化及Ficher合成法等。然而这些合成方法通常需要先经多步反应形成吲哚或吲哚啉骨架,存在反应条件比较苛刻,反应试剂比较昂贵等问题。
因此,有必要提供一种新的合成2,3-二取代吲哚啉类化合物的方法。
发明内容
本发明旨在至少解决现有技术中存在的技术问题之一。为此,本发明提出一种2,3-二取代吲哚啉类化合物的制备方法。
本发明的第一方面实施例提供一种2,3-二取代吲哚啉类化合物的制备方法,包括如下步骤:
将式2所示的化合物与式3所示的化合物在铜催化剂和溶剂存在下进行反应,得到式1化合物;
其中:
R包括取代或未取代的苯基、C1~8的烷基、卤素;
R1包括取代或未取代苯基、取代或未取代的萘基、C1~8的烷基、苄基、杂环取代基;
R2包括氢、卤素、C1~8的烷基。
根据本发明实施例的,至少具有如下有益效果:
本发明由式2所示的化合物与式3所示的化合物在铜催化剂和溶剂存在下进行反应,通过一锅法,即可制备式1的2,3-二取代吲哚啉类化合物,该制备方法的原料廉价易得、操作方便、产率高。除了最终产物外,一系列转化过程中的中间体均无需分离和纯化,能减少资金和劳动力的投入,提供了一种简洁高效的制备方法。
本发明的方法是一种前所未有的铜催化式2所示的化合物与式3所示的化合物的级联反应,产率中等至优异,具有良好的化学、区域和非对映选择性。重要的是,式3所示的氧硫叶立德化合物的铜卡宾表现出与重氮铜卡宾完全不同的反应性。
根据本发明的一些实施例,所述铜催化剂包括三氟甲磺酸铜、溴化亚铜或溴化铜中的至少一种。
根据本发明的一些实施例,所述溶剂包括四氢呋喃、二氯甲烷、甲醇、二氯乙烷或甲苯中的至少一种。
根据本发明的一些实施例,所述式2所示的化合物、所述式3所示的化合物和铜催化剂的摩尔比为1:1~5:0.01~0.3。
根据本发明的一些实施例,所述式2所示的化合物、所述式3所示的化合物和铜催化剂的摩尔比为1:4:0.2。
根据本发明的一些实施例,所述反应的温度为20℃~100℃。
根据本发明的一些实施例,所述反应的时间为2h~48h。
根据本发明的一些实施例,R包括取代或未取代苯基、C1~6的烷基、卤素。
根据本发明的一些实施例,所述取代苯基包括单取代苯基和多取代苯基。
根据本发明的一些实施例,所述反应在惰性气氛中进行。
根据本发明的一些实施例,所述惰性气氛包括氩气、氮气中的至少一种。
根据本发明的一些实施例,所述反应还包括将制备得到的所述式1化合物进行提纯的步骤。
根据本发明的一些实施例,所述提纯可以采用本领域的常规方法,例如柱层析法、液相色谱法等。
根据本发明的一些实施例,所述式3所示的化合物包括但不限于如下结构:
定义和一般术语
“C1-8的烷基”表示碳原子总数为1-8的烷基,包括C1-8的直链烷基、C1-8的支链烷基和C3-8的环烷基,例如可以为碳原子总数为1、2、3、4、5、6、7或8的直链烷基、碳原子总数为1、2、3、4、5、6、7或8的支链烷基或者碳原子总数为3、4、5、6、7或8的环烷基,例如可以为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、环丙基、甲基环丙基、乙基环丙基、环戊基、甲基环戊基、环己基等。针对“C1-6的烷基”具有与此相似的解释,所不同的是,碳原子数不同。
“卤素”包括氟、氯、溴、碘中的任意一个或两个以上。
“杂环取代基”表示该杂环中的成环原子中含有杂原子,且杂原子数为1-3个,以及杂原子选自N、O和S中的至少一种,例如吖啶基、咔唑基、噌啉基、喹喔啉基、吡唑基、吲哚基、苯并***基、呋喃基、噻吩基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、四氢喹啉。
“取代或未取代的苯基”表示苯基上有至少一个H被本文定义的相应基团所取代。
“取代或未取代的萘基”具有相似的定义,萘基中任选有至少一个H被本文定义的相应基团所取代。
本文使用的“取代或未取代的”是指基团可以被或可以不被一个或更多个选自以下的基团进一步取代:烷基、烯基、炔基、芳基、卤素、卤代烷基、卤代烯基、卤代炔基、卤代芳基、羟基、烷氧基、烯氧基、芳氧基、苄氧基、卤代烷氧基、卤代烯氧基、卤代芳氧基、硝基、硝基烷基、硝基烯基、硝基炔基、硝基芳基、硝基杂环基、氨基、烷基氨基、二烷基氨基、烯基氨基、炔基氨基、芳基氨基、二芳基氨基、苯基氨基、二苯基氨基、苄基氨基、二苄基氨基、肼基、酰基、酰氨基、二酰氨基、酰氧基、杂环基、杂环氧基、杂环基氨基、卤代杂环基、羧基酯、羧基、羧基酰胺、巯基、烷硫基、苄硫基、酰硫基和含磷基团。
本发明的其它特征和优点将在随后的说明书中阐述,并且,部分地从说明书中变得显而易见,或者通过实施本发明而了解。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解,其中:
图1为本发明实施例1制得的产物1a的1H NMR谱图;
图2为本发明实施例1制得的产物1a的13C NMR谱图;
图3为本发明实施例2制得的产物1b的1H NMR谱图;
图4为本发明实施例2制得的产物1b的13C NMR谱图;
图5为本发明实施例3制得的产物1c的1H NMR谱图;
图6为本发明实施例3制得的产物1c的13C NMR谱图;
图7为本发明实施例4制得的产物1d的1H NMR谱图;
图8为本发明实施例4制得的产物1d的13C NMR谱图;
图9为本发明实施例5制得的产物1e的1H NMR谱图;
图10为本发明实施例5制得的产物1e的13C NMR谱图;
图11为本发明实施例6制得的产物1f的1H NMR谱图;
图12为本发明实施例6制得的产物1f的13C NMR谱图。
具体实施方式
以下是本发明的具体实施例,并结合实施例对本发明的技术方案作进一步的描述,但本发明并不限于这些实施例。
本发明所采用的试剂、方法和设备,如无特殊说明,均为本技术领域常规试剂、方法和设备。
下面实施例1~6中使用到的式3化合物可以通过购买得到,也可以通过如下方法制备得到。
在干燥的50mL的圆底烧瓶中,加入四氢呋喃溶液,三甲基亚砜(3.0equiv)和叔丁醇钾(3.9equiv),加热回流两小时。之后将反应冷却至0℃,之后化合物4(1.0equiv)溶于四氢呋喃溶液中逐滴添加入反应液中,反应在室温中搅拌,直至酰氯消失。之后在反应中加水,反应混合物用乙酸乙酯萃取。用盐水清洗合并有机相。收集有机层,通过无水硫酸钠上干燥,反应液在减压下浓缩合并,并通过柱层析纯化残余物,得到式3化合物。
下面实施例1~6中使用到的式2化合物可以通过如下方法制备得到。
在100mL圆底烧瓶中,将化合物I,不同取代基的磺酰基氯(1.2equiv),4-二甲氨基吡啶(1.2equiv)和吡啶(5.0equiv)溶于二氯甲烷溶液中,室温下搅拌1 2h。反应液用盐酸萃取,用盐水清洗合并有机相。收集有机层,通过无水硫酸钠上干燥,反应液在减压下浓缩合并,并通过柱层析纯化残余物,得到化合物II。
化合物II溶于N,N-二甲基甲酰胺,然后在0℃下加入氢化钠(2.5equiv)后,将反应移至室温,搅拌1h,之后缓慢滴加二溴乙烷(4.0equiv)。将混合物加热至80℃至完全反应。反应液用水淬灭,用乙酸乙酯萃取,用盐水清洗合并有机相。收集有机层,通过无水硫酸钠上干燥,反应液在减压下浓缩合并,并通过柱层析纯化残余物,得到化合物III。
化合物III溶于二甲基亚砜中,慢慢加入叔丁醇钾(1.5equiv.)。在室温下反应,反应结束后。反应物用水淬灭,然后乙酸乙酯萃取,用盐水清洗合并有机相。收集有机层,通过无水硫酸钠上干燥,反应液在减压下浓缩合并得到化合物IV,未经纯化直接用于下一步。
氩气环境下,于100mL两口瓶中加入双(三苯基膦)氯化钯(2mol%)、碘化亚铜(2mol%)、三苯基膦(5mol%)、化合物IV、三甲基硅基乙炔(1.5equiv)和三乙胺溶液。油浴加热90℃过夜反应。将混合物冷却至室温,使用硅藻土过滤,旋干溶剂。柱层析纯化后得到化合物V。
化合物V溶于甲醇,加入K2CO3(1.1equiv),在室温下反应半小时直到完成。将甲醇旋干,乙酸乙酯萃取,用盐水清洗合并有机相。收集有机层,通过无水硫酸钠上干燥,反应液在减压下浓缩合并,并通过柱层析纯化残余物,得到式2化合物。
实施例1
实施例1提供一种2,3-二取代吲哚啉类化合物的制备方法,反应过程和制备方法如下所示:
氩气环境下,在25mL耐压管瓶中将含催化剂(45mg,0.2mmol)、1,6烯炔类化合物2a(297mg,1.0mmol)和氧硫叶立德类化合物3a(785mg,4.0mmol)溶于二氯乙烷(8.0mL)溶液中,并在80℃下搅拌24h。反应完全后冷却至室温,除去溶剂后粗产品利用硅胶柱层析分离得到白色固体产物1a(379mg,产率:71%)。
如图1和图2所示,所得产品1a的检测数据如下:1H NMR(500MHz,CDCl3):δ7.97(d,J=7.5Hz,2H),7.92(d,J=7.4Hz,2H),7.73–7.70(m,3H),7.63(t,J=7.4Hz,1H),7.58(t,J=7.4Hz,1H),7.53–7.47(m,4H),7.32(t,J=7.7Hz,1H),7.28(d,J=8.1Hz,2H),7.12(dd,J=15.0,11.0Hz,1H),7.06(t,J=7.5Hz,1H),6.97(d,J=7.4Hz,1H),6.86(d,J=15.1Hz,1H),6.06(dd,J=15.0,11.1Hz,1H),5.51(dd,J=15.0,8.7Hz,1H),5.33(d,J=4.3Hz,1H),3.91(dd,J=8.6,4.2Hz,1H),2.38(s,3H);13C NMR(125MHz,CDCl3):δ193.9,190.3,145.0,142.9,141.8,141.3,137.9,134.6,134.1,134.0,133.1,130.8,130.5,130.1,129.5,129.1,128.8,128.5,127.6,126.5,125.7,124.8,116.1,70.8,49.3,21.7;HRMS(ESI):calcd.for[M+Na]+C33H27NO4SNa+556.1553;found 556.1556。
实施例2
实施例2提供一种2,3-二取代吲哚啉类化合物的制备方法,反应过程和制备方法如下所示:
氩气环境下,在25mL耐压管瓶中将含催化剂(45mg,0.2mmol)、1,6烯炔类化合物2a(297mg,1.0mmol)和氧硫叶立德类化合物3b(1173mg,4.0mmol)溶于二氯乙烷(8.0mL)溶液中,并在80℃下搅拌24h。反应完全后冷却至室温,除去溶剂后粗产品利用硅胶柱层析分离得到黄色固体产物1b(487mg,产率:67%)。
如图3和图4所示,所得产品1b的检测数据如下:1H NMR(500MHz,CDCl3):δ7.79(t,J=8.0Hz,1H),7.73(d,J=8.1Hz,1H),7.68–7.62(m,3H),7.45(dd,J=8.4,1.7Hz,1H),7.42–7.40(m,1H),7.39(dd,J=3.2,1.8Hz,1H),7.36–7.31(m,2H),7.23(d,J=8.1Hz,2H),7.06(td,J=7.5,0.8Hz,1H),7.04–6.96(m,2H),6.60(dd,J=15.1,3.0Hz,1H),5.82(dd,J=14.9,11.1Hz,1H),5.55(dd,J=15.0,7.7Hz,1H),5.26(dd,J=3.3,1.0Hz,1H),4.01–3.52(m,1H),2.33(s,3H);13C NMR(125MHz,CDCl3):δ191.7(d,J=5.4Hz),187.5(d,J=2.8Hz),161.2(d,J=255.7Hz),160.9(d,J=256.6Hz),145.0,143.7,143.2,141.7,134.6,133.0(d,J=3.6Hz),132.2(d,J=3.5Hz),130.4,130.0,129.8,129.5,129.3(d,J=10.0Hz),129.0(d,J=7.3Hz),128.9(d,J=3.0Hz),128.3(d,J=3.5Hz),127.7(d,J=9.8Hz),127.4,125.8,125.7,125.6,124.8,122.0(d,J=13.7Hz),120.3(dd,J=27.1,4.3Hz),116.2,73.3(d,J=7.5Hz),48.18,21.66;HRMS(ESI):calcd.for[M+H]+C33H24Br2F2NO4S+725.9755;found 725.9756。
实施例3
实施例3提供一种2,3-二取代吲哚啉类化合物的制备方法,反应过程和制备方法如下所示:
具体制备过程为:
氩气环境下,在25mL耐压管瓶中将含催化剂(45mg,0.2mmol)、1,6烯炔类化合物2a(297mg,1.0mmol)和氧硫叶立德类化合物3c(745mg,4.0mmol)溶于二氯乙烷(8.0mL)溶液中,并在80℃下搅拌24h。反应完全后冷却至室温,除去溶剂后粗产品利用硅胶柱层析分离得到白色固体产物1c(390mg,产率:76%)。
如图5和图6所示,所得产品1c的检测数据如下:1H NMR(500MHz,CDCl3):δ7.77(d,J=8.1Hz,1H),7.69–7.67(m,3H),7.65–7.62(m,1H),7.45(d,J=3.6Hz,1H),7.34(t,J=7.8Hz,1H),7.26(dd,J=6.0,1.8Hz,3H),7.16(dd,J=15.1,11.1Hz,1H),7.09(t,J=7.4Hz,1H),7.00(d,J=7.5Hz,1H),6.73(d,J=15.2Hz,1H),6.61(dd,J=3.6,1.6Hz,1H),6.59(dd,J=3.5,1.6Hz,1H),5.96(dd,J=15.0,11.1Hz,1H),5.61(dd,J=15.0,8.0Hz,1H),5.08(d,J=4.4Hz,1H),4.00(dd,J=7.9,4.4Hz,1H),2.37(s,3H);13C NMR(125MHz,CDCl3):δ183.5,177.9,153.5,150.3,147.6,146.8,145.1,142.3,142.1,141.8,134.0,130.9,130.1,130.0,129.4,127.6,125.7,125.4,124.9,120.1,117.7,116.3,113.0,112.7,71.0,49.2,21.7;HRMS(ESI):calcd.for[M+H]+C29H24NO6S+514.1319;found514.1324。
实施例4
实施例4提供一种2,3-二取代吲哚啉类化合物的制备方法,反应过程和制备方法如下所示:
具体制备过程为:
氩气环境下,在25mL耐压管瓶中将含催化剂(45mg,0.2mmol)、1,6烯炔类化合物2a(297mg,1.0mmol)和氧硫叶立德类化合物3d(697mg,4.0mmol)溶于二氯乙烷(8.0mL)溶液中,并在80℃下搅拌24h。反应完全后冷却至室温,除去溶剂后粗产品利用硅胶柱层析分离得到黄色油状产物1d(284mg,产率:58%)。
如图7和图8所示,所得产品1d的检测数据如下:1H NMR(500MHz,CDCl3):δ7.77(d,J=8.1Hz,1H),7.51(d,J=8.3Hz,2H),7.32(t,J=7.8Hz,1H),7.17(d,J=8.2Hz,2H),7.10(t,J=7.5Hz,1H),6.99(d,J=7.5Hz,1H),6.63(dd,J=15.5,10.9Hz,1H),5.89(d,J=15.5Hz,1H),5.70(dd,J=15.1,10.9Hz,1H),5.04(dd,J=15.1,7.9Hz,1H),4.27(d,J=3.0Hz,1H),4.02–3.95(m,2H),3.45–3.32(m,1H),2.44–2.38(m,1H),2.36(s,3H),2.30–2.21(m,2H),2.20–2.06(m,4H),2.04–1.80(m,4H),1.80–1.73(m,1H);13C NMR(125MHz,CDCl3):δ209.3,201.1,145.1,141.9,141.3,141.1,133.6,132.2,129.9,129.3,129.2,128.3,127.6,125.9,125.5,117.4,73.6,47.9,44.1,42.5,25.6,24.7,24.6,24.0,21.7,18.0,17.9;HRMS(ESI):calcd.for[M+H]+C29H32NO4S+490.2047;found 490.2045。
实施例5
实施例5提供一种2,3-二取代吲哚啉类化合物的制备方法,反应过程和制备方法如下所示:
具体制备过程为:
氩气环境下,在25mL耐压管瓶中将含催化剂(45mg,0.2mmol)、1,6烯炔类化合物2b(362mg,1.0mmol)和氧硫叶立德类化合物3a(785mg,4.0mmol)溶于二氯乙烷(8.0mL)溶液中,并在80℃下搅拌24h。反应完全后冷却至室温,除去溶剂后粗产品利用硅胶柱层析分离得到白色固体产物1e(347mg,产率:58%)。
如图9和图10所示,所得产品1e的检测数据如下:1H NMR(500MHz,CDCl3):δ7.97(d,J=7.5Hz,2H),7.93(d,J=7.4Hz,2H),7.73(d,J=8.5Hz,2H),7.65–7.60(m,4H),7.59–7.56(m,1H),7.53–7.46(m,4H),7.32(t,J=7.8Hz,1H),7.23(dd,J=14.8,3.8Hz,1H),7.07(t,J=7.5Hz,1H),7.01(d,J=7.4Hz,1H),6.86(d,J=15.1Hz,1H),5.99(dd,J=15.0,10.9Hz,1H),5.86(dd,J=15.0,8.1Hz,1H),5.42(d,J=4.4Hz,1H),3.96(dd,J=8.0,4.4Hz,1H);13C NMR(125MHz,CDCl3):δ193.7,190.3,142.5,141.4,140.8,137.8,136.8,134.2,133.9,133.1,132.6,131.1,130.4,129.5,129.14,129.11,129.02,128.96,128.8,128.5,126.9,126.0,124.9,115.5,70.9,49.1;HRMS(ESI):calcd.for[M+H]+C32H25BrNO4S+598.0682;found 598.0682。
实施例6
实施例6提供一种2,3-二取代吲哚啉类化合物的制备方法,反应过程和制备方法如下所示:
具体制备过程为:
氩气环境下,在25mL耐压管瓶中将含催化剂(45mg,0.2mmol)、1,6烯炔类化合物2c(346mg,1.0mmol)和氧硫叶立德类化合物3a(785mg,4.0mmol)溶于二氯乙烷(8.0mL)溶液中,并在80℃下搅拌24h。反应完全后冷却至室温,除去溶剂后粗产品利用硅胶柱层析分离得到白色固体产物1f(384mg,产率:66%)。
如图11和图12所示,所得产品1f的检测数据如下:1H NMR(500MHz,CDCl3):δ7.96–7.92(m,4H),7.74(s,1H),7.70(d,J=8.2Hz,2H),7.63(t,J=7.4Hz,1H),7.58(t,J=7.4Hz,1H),7.53–7.47(m,4H),7.30(d,J=8.1Hz,2H),7.09(dd,J=15.0,11.0Hz,1H),6.87(d,J=15.1Hz,1H),6.81(s,1H),6.03(dd,J=15.0,11.1Hz,1H),5.43(dd,J=15.0,8.6Hz,1H),5.31(d,J=4.0Hz,1H),3.83(dd,J=8.5,3.8Hz,1H),2.39(s,3H),2.27(s,3H);13C NMR(125MHz,CDCl3):δ193.5,190.2,145.2,142.7,140.9,140.7,137.8,135.2,134.4,134.1,133.9,133.2,132.5,130.6,130.2,129.5,129.1,129.0,128.8,128.5,127.51,127.49,126.6,116.7,71.0,48.9,21.7,20.0;HRMS(ESI):calcd.for[M+H]+C34H29ClNO4S+582.1500;found 582.1500。
实施例7
实施例7的制备方法同实施例1,主要探究不同催化剂对反应的影响。
催化剂 | 产率/% |
实施例1 | 52 |
溴化亚铜 | 28 |
氯化亚铂 | 0 |
醋酸铑 | 0 |
环戊二烯双(三苯基磷)氯化钌 | 0 |
三苯基膦金(I)双三氟甲烷磺酰亚胺 | 0 |
氯化铁 | 0 |
溴化钴 | 0 |
溴化镍 | 0 |
实施例8
实施例8的制备方法同实施例1,主要探究不同温度对反应的影响。
温度/℃ | 产率/% |
60 | 52 |
实施例1 | 71 |
100 | 58 |
对比例1
对比例1的制备方法完全和实施例1相同,其区别在于,用化合物5替换化合物3,反应式如下所示,结果,并不能合成本申请的化合物。
因此,式5重氮化合物与式2化合物并不发生反应,由此,可以说明本发明的式3化合物的铜卡宾表现出与重氮铜卡宾完全不同的反应性,即式5化合物不能与式2化合物进行反应。
上面结合本发明实施例作了详细说明,但本发明不限于上述实施例,在所属技术领域普通技术人员所具备的知识范围内,还可以在不脱离本发明宗旨的前提下作出各种变化。
Claims (6)
1.一种2,3-二取代吲哚啉类化合物的制备方法,其特征在于,包括如下步骤:
将式2所示的化合物与式3所示的化合物在铜催化剂和溶剂存在下进行反应,得到式1化合物;
;
其中,所述式1化合物选自化合物1a~1f中的一种:
;
所述式2所示的化合物与式3所示的化合物中的R、R1和R2与式1化合物中结构式的基团相对应;
所述铜催化剂选自三氟甲磺酸铜、溴化亚铜或溴化铜中的至少一种;
所述溶剂选自四氢呋喃、二氯甲烷、甲醇、二氯乙烷或甲苯中的至少一种;
所述反应的温度为20℃~100 ℃。
2.根据权利要求1所述的2,3-二取代吲哚啉类化合物的制备方法,其特征在于,所述式2所示的化合物、所述式3所示的化合物和铜催化剂的摩尔比为1:1~5:0.01~0.3。
3.根据权利要求2所述的2,3-二取代吲哚啉类化合物的制备方法,其特征在于,所述式2所示的化合物、所述式3所示的化合物和铜催化剂的摩尔比为1:4:0.2。
4.根据权利要求1所述的2,3-二取代吲哚啉类化合物的制备方法,其特征在于,所述反应的时间为2 h~48 h。
5.根据权利要求1所述的2,3-二取代吲哚啉类化合物的制备方法,其特征在于,所述反应在惰性气氛中进行。
6.根据权利要求1所述的2,3-二取代吲哚啉类化合物的制备方法,其特征在于,还包括将制备得到的所述式1化合物进行提纯的步骤。
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